Discovery Of FTO Gene Mechanism Could Help Develop Anti-Obesity Therapy

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Researchers have discovered the physiological and cellular functioning of the FTO gene, associated with obesity and type II diabetes.

Discovery Of FTO Gene Mechanism Could Help Develop Anti-Obesity Therapy

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An international team led by University of Chicago chemistry professor Chuan He has shown, for the first time, the existence of the reversible RNA modification process called methylation.

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The process potentially impacts protein expression and function through its action on a common RNA base: adenosine. The process is reversible because it can involve the addition or removal of a methyl group from adenosine. The team found that the FTO protein mediates cellular removal of the methyl group.

He and 10 co-authors from Chicago, China and England published the details of their finding in the Oct. 16 advance online edition of Nature Chemical Biology.

"An improved understanding of the normal functions of FTO, as exemplified by this work, could aid the development of novel anti-obesity therapies," said Stephen O'Rahilly, professor of clinical biochemistry and director of the Metabolic Research Laboratories at the University of Cambridge. O'Rahilly.

"Variants around the FTO gene have consistently been associated with human obesity and artificial manipulation of the FTO gene in mice clearly demonstrates that it plays a crucial role in the regulation of body weight," O'Rahilly explained. "However, the development of a deeper understanding of the normal biological role of FTO has been challenging."

Scientists already had demonstrated that FTO removes methyl groups from nucleic acids, but only on one rare type of DNA or RNA methylation. The new research from He and his colleagues shows that FTO also acts on the common messenger RNA modification called N6-methyladenosine, O'Rahilly said.

The paper arose from He's investigations of the AlkB family of proteins that act on nucleic acids. Based on this work, He and his collaborators proved that human cells exhibit reversible methylation of RNA bases, which significantly impact critical life processes.

Every human messenger RNA carries on average three to six methylations on adenosine. Scientists knew these methylations were extremely important but their function remained a mystery, He said. "For the first time, we show that these methylations are reversible and play a key role in human energy homeostasis," the process by which the body maintains a complex biochemical dynamic equilibrium.

The modification of N6-methyladenosine in messenger RNA is pervasive throughout the mammal kingdom and many other organisms. Despite its abundance, this modification's exact functional role remains unknown, He said. But his team's discovery strongly indicates that the modification has major roles in messenger RNA metabolism.

The finding may open a new research field — RNA epigenetics — for delving into the realm of biological regulatory processes, He said.

DNA (deoxyribonucleic acid) for decades has reigned as king over biological research on epigenetics of nucleic acids, but RNA modification has secretly wielded a far greater genetic influence than anyone had previously suspected. That's why, as He wrote last year, "reversible RNA modification might represent another realm for biological regulation in the form of 'RNA epigenetics.'"

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